Two important events in the cell division cycle are the duplication of the chromosomal DNA and the separation of the duplicated chromosomes. These events occur in two discrete phases: the synthetic phase (S-phase) and the mitotic phase (M-phase), which are separated from each other by distinct gaps in time, gap 1 (G1) and gap 2 (G2). The proper coordination of these events is achieved by checkpoint pathways that delay the progression of the cell cycle when proper completion of one phase is disrupted by physical damage or other means. Under normal circumstances, if the extent of damage is irreparable, most cells initiate a sequence of biochemical events leading to programmed cell death or apoptosis. Deregulation in any one or more of these checkpoint mechanisms sometimes leads to genetic instability which is a primary step for a tumor to evolve into invasive malignant state. The chemotherapeutic management of various cancers is achieved by drugs that block either the S-phase, the M-phase, or that block regulatory or metabolic pathways impinging upon the cell cycle machinery. For example, some drugs affect the functions or structures of DNA or RNA, others interfere with enzymes involved in folate, purine, or pyrimidine metabolism, or the function of mitotic spindles. Anti-mitotic drugs such as vinica akaloids and taxoids can arrest cells in M-phase by interacting with mitotic spindle components, microtubules. Microtubules are one of the major filamentous components of the cytoskeleton, and, together with actin and intermediate filaments, they organize the cellular cytoplasm. In interphase cells a dynamic radial array of microtubules emanates from the centrosome at the cell center. In this array, the fast growing and fast shrinking plus ends of microtubules project distally from the center. During mitosis, the duplicated centrosomes nucleate assembly of much more dynamic and more numerous polymers as they move apart to form the opposite poles of the mitotic spindle. The increased dynamics and number of microtubules enhance the chance-encounter of growing microtubules with the primary construction of the duplicated chromatid pairs. Upon attaching to microtubules, chromosomes undergo a series of movements eventually leading to their conversion and final assembly at the mid-plate during metaphase. The onset of the next event in mitosis, the anaphase, is delayed until each of the chromatid pairs is assembled at the metaphase mid-plate and proper tension is generated on the attached sister chromatids.
Dynamic assembly or disassembly of microtubules is required for the morphogenesis of mitotic spindle. Accordingly, small organic molecules that modulate the dynamics of microtubules primarily because some of the microtubule interacting agents are useful for chemotherapeutic management of certain kinds of tumors. There are two classes of these anti-microtubule agents: those that prevent the assembly of tubulin, and those that promote the assembly of tubulin. A prototypic example of a potent assembly inhibitor is colchicine. Others are analogs of colchicine such as podophyllotoxin, MTC [(2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one)], TCB (2,3,4-trimethoxy-4xe2x80x2-carbomethoxy-1,1xe2x80x2-biphenyl) and TKB (2,3,4-trimethoxy-4xe2x80x2-acetyl-1,1xe2x80x2-biphenyl), and vinica akaloids. Taxol and its analogs represent a class of compounds that promote the assembly of microtubules. It is now clear that although all of these microtubule drugs prevent cell division, only a select few have been useful clinically. In addition, there are differences regarding the toxicity and the efficacy of these drugs for distinct classes of tumors.
Applicants have discovered that the antitussive noscapine and its derivatives are useful in the treatment of neoplastic diseases. Noscapine is used as an antitussive drug and has low toxicity in humans. Noscapine arrests mammalian cells at mitosis, causes apoptosis in cycling cells, and has potent antitumor activity. Noscapine is an alkaloid from opium, and is readily available as a commercial byproduct in the commercial production of prescription opiates. Applicants have unexpectedly discovered that noscapine promotes assembly of tubulin subunits.